1. Field of the Invention
The present invention relates generally to the pharmacology and medical therapeutics of irritable bowel syndrome and related bowel diseases. More specifically, the present invention relates to the uses of luminally active anti-inflammatory or immunosuppressive compounds with minimal or no systemic side effects, for treatment of irritable bowel syndrome and related disorders.
2. Description of the Related Art
Irritable Bowel Syndrome is characterized, in part, by painful defecation and altered stool frequency/consistency and has a reported prevalence between 15-25% in both the industrialized and developing world. See Malcolm A, Kellow J E. Irritable Bowel Syndrome. MJA 1998; 169:274-279. Irritable Bowel Syndrome, unlike most other diseases of the gastrointestinal tract, is not characterized by any specific, currently known histopathological changes, but rather is a functional disorder characterized, in part, by disturbed gut motility and/or abdominal pain perception linked to cytokines and/or other inflammatory cascades. See Collins S M, et al., Stress, inflammation and the irritable bowel syndrome. Can J Gastroenterol 1999: 13; A:47A-49A. Irritable Bowel Syndrome also occurs in Inflammatory Bowel Disease (IBD) patients who are in remission from their symptoms, see Collins S M, et al. “Putative inflammatory and immunological mechanisms in functional bowel disorders” Baillieres Best Pract Res Clin Gastroenterol 1999: 13; 429-436.
The precise pathophysiology of irritable bowel syndrome is not well understood. Nevertheless, there is a heightened sensitivity to visceral pain perception in irritable bowel syndrome, known as “peripheral sensitization”. This sensitization involves a reduction in the threshold and an increase in the gain of the transduction processes of primary afferent neurons, attributable to a variety of mediators including monoamines (both catecholamines and indoleamines), substance P, and variety of cytokines and prostanoids including the E-type prostaglandins. See Mayer et al.: “Basic and clinical aspects of visceral hyperalgesia” Gastroenterology 1994; 107:271-293. Also implicated in the etiopathology of irritable bowel syndrome is intestinal motor dysfunction (gut dysmotility) which leads to abnormal handling of intraluminal contents and/or gas. See Kellow et al., “Altered small bowel motility in irritable bowel syndrome is correlated with symptoms” Gastroenterlogy 1987; 92:1885-1893; Levitt et al., “The relation of passage of gas and abdominal bloating to colonic gas production.” Ann Int Med 1996; 124:422-4. Psychological factors may also contribute to irritable bowel syndrome symptoms appearing in conjunction with, if not triggered by, disturbances including depression and anxiety. See Drossman et al., “Psychosocial aspects of the functional bowel disorders” Gastroenterlogy Int 1995; 8:47-90.
Although the etiology of irritable bowel syndrome is not fully characterized, validated diagnostic schemata for irritable bowel syndrome are available. For example, the Rome criteria and the Manning criteria allow the diagnosis of irritable bowel syndrome to be made based upon patient history. As an example, the Rome criteria requires three months of continuous or recurrent abdominal pain or discomfort that is relieved by defecation and/or associated with a change in stool frequency or consistency as well as two or more of the following: altered stool frequency, altered stool form, altered stool passage, passage of mucus, or bloating and abdominal distention. The absence of any structural or biochemical disorders that could be causing the symptoms is also a necessary condition.
Irritable bowel syndrome represents a therapeutic challenge to both clinicians and developers of pharmaceuticals. The uncertainty and variety of causes, as well as the variable nature of symptomatic expression greatly complicates the task of treating this disorder. As noted above, irritable bowel syndrome is a functional bowel disorder that is characterized by, for example, abdominal pain and/or discomfort in association with abnormal stool frequency and/or consistency, for example, diarrhea or constipation.
The earliest and most simple treatments have focused on symptomatic relief. For diarrhea-predominant irritable bowel syndrome, anti-diarrheal agents such as loperamide and diphenoxylate have been used with some success, especially in acute, situation-specific settings. See Efskind et al., “A double blind, placebo-controlled trial with loperamide in irritable bowel syndrome” Scand J Gastroenterol 1996; 31:463-8. Dietary supplementation with fiber or psyllium products has typically been recommended to irritable bowel syndrome patients, particularly those with constipation-predominant symptoms. More recent studies, however have cast some doubt on the real benefit provided by this strategy. See Lucy et al., “Is bran efficacious in irritable bowel syndrome? A double blind, placebo-controlled, crossover study” Gut 1987; 28:221-25; Frances C Y, Whorwell P J: “Bran and irritable bowel syndrome: time for reappraisal” Lancet 1994; 34:496-500.
More aggressive treatments for constipation-predominant symptoms include lactulose, docusate, and prokinetic agents such as cisapride. See Shutze et al., “Double-blind study of the effect of cisapride on constipation and abdominal discomfort as components of the irritable bowel syndrome” Aliment Pharmacol Ther 1997; 1 1:387-94. Symptomatic relief of the pain associated with irritable bowel syndrome has been attempted with a variety of smooth muscle relaxants/antispasmodics as well as anticholinergic agents. Meta-analyses of these studies indicate an efficacy greater than placebo for five agents: cimetropium bromide (antimuscarinic), primaverium/octolinium bromide (calcium antagonists), tremebutine (peripheral opiate antagonist), and mebeverine (anticholinergic). See Klein K B: “Controlled treatment trials in the irritable bowel syndrome” Gastroenterology 1988; 95:232-241; Poynard T, Naveu S, Mory B: “Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel” Aliment Pharmacol Ther 1994; 8:499-510.
There are a number of prokinetic agents that have been examined in the treatment of irritable bowel syndrome. Such investigational prokinetic agents include nitric oxide synthase inhibitors, adrenoceptor antagonists, gonadotropin-releasing hormone (GnRH) analogues such as leuprolide, cholecystokinin-a (CCK.sub.A) antagonists, and certain opioid receptor antagonists. See DePonti et al., “Adrenergic mechanisms in the control of gastrointestinal motility: from basic science to clinical applications” Pharmacol Ther 1996; 69:59-78; Tonini M: “Recent advances in the pharmacology of gastrointestinal prokinetics” Pharmacol Res 1996; 33:216-26; Mathias et al., “Effect of leuoprolide acetate in patients with functional bowel disease. Long term follow up after double blind, placebo-controlled study” Dig Dis Sci 1994; 39:1155-62; Wettstein et al., “CCK antagonists: pharmacology and therapeutic interest” Pharmacol Ther 1994; 62:267-82; Evans et al., “LY247636: a selective antagonist for peripheral mu opioid receptors” Gastroenterology 1994; 106:A495. Adrenergic beta.sub.3 selective agonists fave also been examined as potential antispasmodic/smooth muscle relaxant. See DePonti et al., “Inhibitory effects of SR58611A on canine colonic motility: evidence for a role of .beta..sub.3-adrenoceptors” Br J Pharmacol 1995; 1 14:1447-1453.
Many newer treatments also focus on targets, both peripheral and central, that are implicated in contributing to the cause and progression of irritable bowel syndrome. As mentioned above, visceral hyperalgesia (characterized by an abnormally low pain threshold in GI afferent sensory neurons) has been implicated in irritable bowel syndrome etiopathology. The role of serotonin (5-HT) and its receptors in the GI tract has also been investigated. While many 5-HT receptor subtypes (5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3 and 5-HT.sub.4) are known to play a role in enteric neuroregulation and perception, research and product development attention has focused, in particular, on the 5-HT.sub.3 receptor, which is known to be present on substances containing afferent neurons within the gut. See Farthing MG: “5-hydroxytriptamine and 5-hydroxytriptamine-3 receptor antagonists” Scand J Gastroenterol 1991; 26:92-100; Galligan J J: “Electrophysiological studies of 5-hydroxytriptamine receptors on enteric neurons” In: Serotonin and Gastrointestinal Function pp 109-126, Gaginella T S and Galligan J J (eds.) CRC Press, Boca Raton. However, while there are several 5-HT.sub.3 antagonists available, including ondansetron (which is an antiemetic) and granisetron, no such antagonist is currently approved by the United States Food and Drug Administration (FDA) for use in treating irritable bowel syndrome, although the FDA has approved Lotronex (alosetron hydrochloride), a potent serotonin 5HT-.sub.3 antagonist, for use in the treatment for diarrhea-predominant irritable bowel syndrome (D-IBS) in women. See Mangel A W, Northcutt A R: “Review article: the safety and efficacy of alosetron, a 5-HT.sub.3 receptor antagonist, in female irritable bowel syndrome patients” Aliment Pharmacol Ther 1999; 13 Suppl.2:77-82. However, after notifying the FDA of post-marketing reports that reported serious adverse events associated with Lotronex, Glaxo Wellcome withdrew Lotronex from the market.
Members of the class of 5-HT.sub.4 receptor antagonists has also been studied in this capacity. See Houghton et al., “5-HT.sub.4 antagonism in irritable bowel syndrome (1BS): effect of SB-207266A on rectal sensitivity and small bowel transit” Gut 1997; 4Suppl.3:A26. In addition, other drugs being examined for their modulation of visceral sensitivity include: (i) the opioid .kappa. receptor agonists such as fedotozine, which, unlike agents which act on opioid .mu. and .delta. receptors (located in the GI tract), does not appear to have undesirable central effects, and, (ii) the somatostatin analogues such as octreotide. See Junien J L, Riviere P: “The hypersensitive gut-peripheral kappa agonists as a new pharmacological approach” Aliment Pharmacol Ther 1995; 9:117-26; Halser et al., “A somatostatin analogue inhibits afferent pathways mediating perception of rectal distention” Gastroenterology 1993; 104:1390-7.
Antidepressants, which have been used for a number of years to treat associated affective disorder in irritable bowel syndrome patients, may address the increased pain perception that many of these patients experience. In particular, the tricyclic antidepressants, which exert useful actions at several locations along the brain-gut axis, may mediate the increased pain perception in these individuals. See Gorard et al., “Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea predominant irritable bowel syndrome” Dig Dis Sci 1995; 40:86-95; Peghini et al., “Imiprimine increases pain and sensation thresholds to esophageal balloon distension in humans” Gastroenterology 1997; 1 12:A255.
Sigma 1 receptor (“.sigma.1,” “sigma,” or “sigma 1”) agonists have been shown to possess antidepressant and anxiolytic properties. In vitro and in vivo studies have demonstrated that sigma 1 sites are implicated in control of motor behavior, regulation of smooth muscle contraction, and control of gut secretions (specifically alkaline secretions), and therefore may alleviate the increased gut motility and increased gut secretions from which many irritable bowel syndrome patients suffer. See Walker et al., “Control of motor behavior” Neurology 1988; 38; 961-965; Vaupel et al., “Regulation of smooth muscle” Eur J Pharmacol 1987; 139; 125-128; Campbell et al., “Regulation of neurotransmitter release” Eur J Pharmacol 1987; 138; 447-449.
As can be seen by the discussion supra, the symptomologies of irritable bowel syndrome are caused by a complex pharmacology. Current treatment options for irritable bowel syndrome and/or related conditions do not adequately address the complexities of irritable bowel syndrome and therefore, current treatments remain inadequate or, as exemplified by the recent withdrawal from the United States market of the serotonin 5HT-.sub.3 antagonist Lotronex (alosetron hydrochloride). A treatment that is effective in treating bowel disorders such as irritable bowel syndrome, without producing severe adverse effects, is therefore desired. More particularly, a treatment for bowel disorders such as irritable bowel syndrome that works via a plurality of pharmacological mechanisms, is desired; such a treatment may be the most efficacious solution to the treatment of irritable bowel syndrome. Novel treatment options that may address one or more of the multiple therapeutic targets associated with irritable bowel syndrome and related bowel disorders or alleviate one or more of the symptomologies of irritable bowel syndrome and the related bowel disorders as described above, are therefore is great demand currently.
The prior art is deficient in an effective treatment for irritable bowel syndrome. The present invention fulfills this longstanding need and desire in the art.